Outcomes following external beam radiotherapy to the prostate and pelvic lymph nodes in addition to androgen deprivation therapy in non-metastatic prostate adenocarcinoma with regional lymph node involvement: a retrospective cohort study

Objective There is a paucity of evidence for external beam radiotherapy (EBRT) in patients with non-metastatic prostate adenocarcinoma with regional lymph nodes (cN1) as primary treatment in addition to androgen deprivation therapy (ADT). We present the retrospective outcomes of cN1 patients treated with prostate and pelvic nodal (PPLN) EBRT and ADT. Methods The clinical records of cN1 patients given PPLN EBRT from January 2012 to January 2020 were retrospectively reviewed. Primary outcomes of overall survival, prostate cancer-specific survival, and failure-free survival were analysed. Secondary outcomes of biochemical relapse-free survival, locoregional recurrence-free survival, and distant metastases-free survival were also reviewed. The prognostic values of clinicopathological parameters were investigated. Treatment toxicity was also reviewed. Results We identified 121 cN1 patients treated with PPLN EBRT and ADT. Treatment was well tolerated, with only a minority (1.7%) having Grade 3 toxicities. 5-year overall survival and prostate cancer-specific survival were 74.4 and 89.1% respectively. 5-year failure-free survival was 55.4%; with 5-year biochemical relapse-free survival, locoregional recurrence-free survival, and distant metastases-free survival at 56.2%, 85.2%, and 65.4% respectively. The benefits of PPLN EBRT were seen in most patients, with prolonged failure-free period and good loco-regional control. Conclusion Patients with cN1 disease should be considered for PPLN EBRT, in addition to ADT. Treatment is well tolerated with low toxicity, good locoregional control, and prolonged time to disease progression. Advances in knowledge We report real-world experience of cN1 patients treated with PPLN EBRT in addition to ADT, with good outcomes following treatment and low toxicity.

with only a few describing EBRT of the PLN in addition to the prostate and seminal vesicles (SVs). Here, we add to the evidence base by describing the outcomes of our cN1 patients treated with prostate and pelvic nodal (PPLN) EBRT within a large hospital within the United Kingdom (UK) using a standard dose fractionation regime in addition to ADT.

Patients
The study was approved by the local audit management board, and patient details were anonymised during data collection and analysis. Data were collected on consecutive cN1 patients referred for PPLN EBRT between January 2012 and January 2020. Patients were referred from within the regional cancer network, covering a population of approximately 2.2 million people. 6 Patients referred for EBRT following prostatectomy, those who had received upfront systemic therapy, and those involved in clinical trials were excluded from analyses.

Staging and pathology
Disease staging followed the seventh edition of the AJCC/UNM staging. 7 All patients had work-up of localised high risk prostate adenocarcinoma; including baseline prostate-specific antigen (PSA), MRI of the pelvis, staging CT, and bone scan. Patients of cN0 or M1 status were excluded from analyses. PLN were considered involved if >10 mm in diameter in the short axis on conventional radiological imaging and following consensus review by our urology multidisciplinary team.

Hormonal therapy
All cN1 patients were started on neo-adjuvant ADT for up to 6 months with a luteinizing hormone-releasing hormone (LHRH) agonist. An anti-androgen was also prescribed for the initial 4 weeks from LHRH agonist initiation. Patients were then consented for delayed PPLN EBRT up to 6 months to allow for maximal cytoreduction. After EBRT, ADT was continued until to 2-3 years.
External beam radiotherapy planning and delivery For EBRT planning, the prostate, SV, and PLN were delineated on the planning system as described by consensus guidance. 8,9 Briefly, for the PLN EBRT volumes, the pelvic iliac vessels were delineated from the lower border of the L5 vertebra down to the obturators stopping 10 mm above the pubic symphysis. This is then expanded circumferentially by 7 mm, editing off muscle and bone, to create the PLN clinical target volume (CTV), and further expanded globally by 5 mm to create the PLN planning target volume (PTV). For the organs at risk (OARs), the anal canal, rectum, bladder, large bowel, small bowel, and both right and left femoral heads were outlined. Patients were asked to keep an empty rectum and comfortably full bladder during CT simulation and EBRT.
EBRT was delivered using intensity modulated radiotherapy (IMRT) via Tomotherapy. As per the PIVOTAL trial 8 (NCT00444821-a Phase II feasibility study of EBRT to the prostate, SV, and PLN vs EBRT to the prostate and SV in high risk cN0 patients) and STAMPEDE trial 10 protocols, the PLN were treated up to 55-60 Gy in 37 fractions (38-55 Gy in EQD2), whilst the prostate and SV were treated up to 74 Gy in 37 fractions (74 Gy in EQD2). All EBRT volumes were treated together via simultaneous integrated boost (SIB) aiming to deliver 95% dose coverage of the PTV. All patients received EBRT as per predefined protocols to ensure dose constraints for the OARs were met. 8 Follow-up Patients were reviewed during EBRT to assess and manage toxicities. Acute and chronic toxicities were recorded as described by the RTOG and European Organisation for Research and Treatment of Cancer. 11 Acute toxicity was defined as adverse effects recorded during EBRT and up to 3 months afterwards, whilst chronic toxicities were defined as adverse effects recorded beyond 3 months.
On completion of EBRT, as per NICE 2008 guidelines, 12 and later the West Midlands Expert Advisory Group guidelines, 13 clinical follow-up consisted of review at 3-, 6-, and 12 months posttreatment. Subsequent reviews were scheduled every 6 months for the second and third year, and annually afterwards. Reviews consisted of clinical assessment, PSA testing, and toxicity assessment for erectile dysfunction and urinary and/or bowel incontinence.

Outcomes
The primary outcomes included 5-year failure-free survival (FFS), overall survival (OS), and prostate cancer-specific survival (PCSS). FFS was defined as the time from PPLN EBRT to the first of either biochemical recurrence, locoregional recurrence, distant metastases, or death from prostate cancer. OS was defined as time from PPLN EBRT until death from any cause, whilst PCSS was defined as time from PPLN EBRT until death from prostate cancer, as recorded within clinical records or death certificates. Patients still alive were censored at last follow-up.
Secondary outcomes included 5-year biochemical relapse-free survival (BRFS), locoregional recurrence-free survival (LRFS), and distant metastases-free survival (DMFS). BRFS was defined as time from PPLN EBRT until biochemical relapse according to the Radiation Therapy Oncology Group-Association of Therapeutic Radiation Oncology (RTOG-ASTRO) Phoenix Consensus Conference Definition (nadir PSA+2). 14 LRFS was defined as the time from PPLN EBRT until detection of recurrent disease within the EBRT field, either at the primary site or locoregional PLN, on radiological imaging. DMFS was defined as the time from PPLN EBRT until detection of recurrent disease beyond the pelvis in other organ sites on radiological imaging. Patients who were failure-free were censored at last follow-up.

Statistical analysis
Data were presented as frequencies, means, and median with ranges. Results of primary and secondary outcomes were displayed using Kaplan-Meier curves, and survival estimates at specific time points were derived from life tables. Comparisons using univariate cox proportional hazard model analyses were conducted to investigate prognostic factors. Threshold for results

Patient characteristics
During the period studied, a total of 318 patients were identified to have received PPLN EBRT from January 2012 to January 2020. Following review, 197 patients were excluded (Figure 1) due to the following: cN1 patients treated with PPLN EBRT but no follow-up data (n = 104), cN0 patients (n = 22), postoperative EBRT (n = 66), and metastatic disease (n = 5). The remaining 121 cN1 patients were included in the final analysis. Demographics, tumour characteristics, and treatment details are summarised in Table 2. Mean PSA before treatment was 32 ng ml −1 (range 3-514), with most presenting with T3 disease (62.8%) and Gleason grade grouping 4 to 5 (71.1%). Majority of patients (76.9%) received a minimum of 2 years of ADT post-EBRT.

Radiotherapy treatment
All patients started on neo-adjuvant ADT for 3-6 months prior to PPLN EBRT and received 37 fractions of EBRT in one phase via SIB ( Figure 2). The prostate and SV were treated to a maximum of 74 Gy EQD2, and the majority (96.7%) received a PLN EBRT dose of at least 43 Gy EQD2 (median dose 51 Gy EQD2). Only two patients (1.7%) received a PLN EBRT dose of <43 Gy EQD2 due to OAR constraints ( Table 2). All patients had on-treatment reviews during EBRT to monitor and manage adverse events.

Morbidity
The majority of patients (94%) had either no toxicities or mild adverse events recorded from PPLN EBRT ( Table 3). The most common recorded toxicities were diarrhoea (41%, worst toxicity was Grade 2 = 10.7%) and cystitis (33%, worst toxicity was Grade 2 = 12.1%), with symptoms resolving after EBRT. Only two patients (1.7%) had toxicities of Grade 3 or more recorded; one patient had Grade 3 proctitis that persisted beyond EBRT, and another had Grade 3 haematuria that eventually settled following treatment. No major bowel complications requiring surgery were recorded.

discussiOn
The cohort of cN1 patients are at high risk of disease progression. 15 The treatment paradigm ranges between locally advanced cN0 patients or metastatic disease. Despite the scarcity of randomised prospective evidence, many clinicians are advocating PPLN EBRT in addition to ADT, 16 and this is now endorsed in multiple guidelines. [17][18][19] We selected a cohort of cN1 patients treated with this approach and demonstrated comparable efficacy and toxicity to other contemporary published studies.
The benefits of EBRT in addition to ADT in cN1 patients has been demonstrated within the STAMPEDE control arm and is accepted within most UK centres. A retrospective subset analysis of 177 cN1 patients from the STAMPEDE control arm included 71 patients that received EBRT and ADT. EBRT volumes included the PLN treated to 45-50 Gy (EQD2) in 58 patients (82%). Estimated outcomes at 5 years were 65% FFS and 82% OS, demonstrating improvement over ADT alone. 4 A much earlier trial, the RTOG 85-31 study, also published a retrospective     27 Furthermore, EBRT dose fractionation was also different, with some delivering up to 55 Gy (EQD2) whilst others employed dose escalation either to the whole pelvis or via local boost to involved PLN. There were differences in time on ADT as well, although all described treatment for at least 12 months. Despite this, all demonstrated the benefits of adding PPLN EBRT alongside ADT in cN1 patients.
Our cN1 patient cohort are similar in clinicopathological parameters to the STAMPEDE cN1 cohort, except for more WHO performance status ≥1 patients involved in our study (Table 2). Overall, PPLN EBRT was well tolerated, with only two incidences of Grade 3 adverse events recorded following a median follow-up of 56 months. Our 5-year outcomes of FFS and OS are comparable to that of STAMPEDE,   From here, the paradigm of future research in cN1 patients continues to evolve. Dose escalation in PPLN EBRT treatment is now possible with the rapid adoption of IMRT, allowing significant sparing of OARs. 31,32 As we demonstrated, there is improved LRFS with higher PLN EBRT doses ≥55 Gy (EQD2), but this did not impact BRFS, DMFS, OS, or PCSS. This is being further investigated in the PRIME trial using moderate and extreme hypofractionation EBRT to the prostate and PLN in high risk cN0 and cN1 patients alongside boost to gross nodal disease. 33 As the few patients who died or had disease progression in our study mostly developed biochemical recurrence followed by distant metastases, this was the driver to poor outcomes. Several trials have sought to mitigate this with the addition of systemic treatment. The GETUG-12 trial and the follow-up of non-metastatic patients from STAMPEDE showed benefit in FFS after adding Docetaxel following EBRT in cN0 and cN1 patients, 34,35 whilst a recent STAMPEDE publication demonstrated increased DMFS with the addition of Abiraterone in high risk non-metastatic prostate adenocarcinoma, of which 39% were cN1 patients. 36 The majority of patients involved here, however, received PPLN EBRT in addition, and we believe this should be the case for most cN1 patients, due to good local control and significant prolongation of the failurefree period.
A strength of our study is that we describe one of the largest retrospective series of cN1 patients treated with PPLN EBRT in addition to ADT, with outcomes in keeping with those seen in the STAM-PEDE and RTOG 85-31 cN1 cohorts. 4,20 Furthermore, we described consistent EBRT dose fractionations with defined treatment volumes and dose constraints. We also demonstrated similar toxicity to PIVOTAL, 8 with most common adverse events recorded as mild and most patients making a full long term recovery ( Table 3). The limitations to our study include biases from retrospective analyses and lack of randomisation, as inherent in retrospective single centre series. 37 We also lacked a cohort of cN1 patients undergoing ADT and/or prostate EBRT alone for comparison. Due to smaller patient numbers, multivariate analyses of prognostic factors were not possible. Toxicity data were also reliant on accurate documentation by clinicians during follow-up, and no formal proforma was used for documentation. Due to these limitations, larger multicentre prospective studies will normally be required to confirm our findings. However, based on the difficulties RTOG 96-08 faced in recruiting patients, it may not be possible to answer this question within a randomised controlled trial.
In this context, our study provides real-world data in the management of cN1 patients receiving PPLN EBRT.

cOnclusiOn
In conclusion, we describe favourable outcomes following PPLN EBRT alongside ADT in one of the largest published cohort of prostate adenocarcinoma patients with cN1 disease. In the absence of randomised control trials investigating PPLN EBRT in such patients, we provide real-world data of this treatment modality, with prolonged LRFS and PCSS seen at 5 years. Treatment was well tolerated, time to disease progression was prolonged, and the majority of patients were rendered failure-free afterwards. Based on these results, prostate adenocarcinoma patients with cN1 disease should be considered for PPLN EBRT, in addition to ADT.
acknOwledgements Special thanks to Ian Stronach, Clinical Scientist, for parsing through the radiotherapy database and collating a list of prostate adenocarcinoma patients for the study.
cOntributOrs AMR and RS contributed to the concept, design, and data acquisition. AMR contributed to the analysis, interpretation of data, and drafting the article. AMR and AZ contributed to revising the article for important intellectual content and final approval of the version to be published.